We, along with others, have shown increased levels of fucosylation with the development of hepatocellular carcinoma (HCC). In an effort to determine the origin of this increased fucosylation, we have performed N-linked glycan analysis of HCC tissue, the surrounding non tumor tissue, and compared this to tissue from a non-diseased adult liver. Surprisingly, no difference in the level of fucosylation was observed from the three donor groups, suggesting that the increased levels of fucosylation observed in the serum of those with HCC is not the result of increased synthesis of fucosylated proteins in the cancer tissue. In addition, the level of fucosylation observed in tissue was much higher than that observed on liver derived serum glycoproteins. On the other hand, increased levels of a tetra-antennary glycan were observed in the HCC tissue as compared to the surrounding tissue or to the non-diseased livers. Recent work by our collaborator has suggested that fucosylation controls the polarized secretion of glycoproteins and directs their secretion apically into the bil. Indeed, bile glycoforms are more heavily fucosylated than in serum and closely resemble those observed in the serum of HCC patients. It is our hypothesis that the over-expression of ? 1,6-N-acetylglucosaminyltransferase V (MGAT-5), which is responsible for the increased branching we have observed, leads to a loss of a tight blood-biliary barrier and the release of fucosylated proteins into the blood. This hypothesis, along with the use of this knowledge to find new biomarkers of HCC, will be tested in 3 aims. First we will examine the role of MGAT-5 in enforcing the polarized secretion of core fucosylated proteins. It is hypothesized that the overexpression of MGAT-5 that we observe in HCC tissue leads to a defect in the blood- biliary barrier and the aberrant release of fucosylated proteins into the blood.
In specific aim 2 we will perform glycoproteomic analysis of bile for markers of HCC. The logic here is that all hepatocytes have the ability to secrete into the blood stream or into the bile capillaries, which eventually forms the bile ducts. Loss of hepatocyte polarity will lead to the aberrant appearance of fucosylated proteins in the blood.
In specific Aim 3 we will examine the ability of our identifid biomarkers to differentiate patients with HCC from patients with liver cirrhosis in a cohort of 1500 patients. The ability of these markers to distinguish HCC from cirrhosis as compared to AFP and other potential biomarkers of HCC will be determined.

Public Health Relevance

The overall goal of this project is an understanding of how changes in glycosylation promote cancer progression and to use this information to identify glycan-based biomarkers for the early detection of cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01CA168856-03
Application #
8695094
Study Section
Special Emphasis Panel (ZCA1-SRLB-4 (M1))
Program Officer
Rinaudo, Jo Ann S
Project Start
2012-08-08
Project End
2017-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
3
Fiscal Year
2014
Total Cost
$311,766
Indirect Cost
$84,208
Name
Drexel University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
002604817
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Betesh, Lucy; Comunale, Mary Ann; Wang, Mengjun et al. (2017) Identification of fucosylated Fetuin-A as a potential biomarker for cholangiocarcinoma. Proteomics Clin Appl 11:
Wang, Mengjun; Sanda, Miloslav; Comunale, Mary Ann et al. (2017) Changes in the Glycosylation of Kininogen and the Development of a Kininogen-Based Algorithm for the Early Detection of HCC. Cancer Epidemiol Biomarkers Prev 26:795-803
Wang, Mengjun; Comunale, Mary Ann; Herrera, Harmin et al. (2016) Identification of IgM as a contaminant in lectin-FLISA assays for HCC detection. Biochem Biophys Res Commun 476:140-5
Holst, Stephanie; Heijs, Bram; de Haan, Noortje et al. (2016) Linkage-Specific in Situ Sialic Acid Derivatization for N-Glycan Mass Spectrometry Imaging of Formalin-Fixed Paraffin-Embedded Tissues. Anal Chem 88:5904-13
Norton, Pamela; Comunale, Mary Ann; Herrera, Harmin et al. (2016) Development and application of a novel recombinant Aleuria aurantia lectin with enhanced core fucose binding for identification of glycoprotein biomarkers of hepatocellular carcinoma. Proteomics 16:3126-3136
Heijs, Bram; Holst, Stephanie; Briaire-de Bruijn, Inge H et al. (2016) Multimodal Mass Spectrometry Imaging of N-Glycans and Proteins from the Same Tissue Section. Anal Chem 88:7745-53
Mehta, Anand; Comunale, Mary Ann; Rawat, Siddhartha et al. (2016) Intrinsic hepatocyte dedifferentiation is accompanied by upregulation of mesenchymal markers, protein sialylation and core alpha 1,6 linked fucosylation. Sci Rep 6:27965
Wang, Mengjun; Devarajan, Karthik; Singal, Amit G et al. (2016) The Doylestown Algorithm: A Test to Improve the Performance of AFP in the Detection of Hepatocellular Carcinoma. Cancer Prev Res (Phila) 9:172-9
Meibalan, Elamaran; Comunale, Mary Ann; Lopez, Ana M et al. (2015) Host erythrocyte environment influences the localization of exported protein 2, an essential component of the Plasmodium translocon. Eukaryot Cell 14:371-84
Zhao, Xuesen; Guo, Fang; Comunale, Mary Ann et al. (2015) Inhibition of endoplasmic reticulum-resident glucosidases impairs severe acute respiratory syndrome coronavirus and human coronavirus NL63 spike protein-mediated entry by altering the glycan processing of angiotensin I-converting enzyme 2. Antimicrob Agents Chemother 59:206-16

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